title: Myeloid calcifying cells promote atherosclerotic calcification via paracrine activity and allograft inflammatory factor-1 overexpression.
abstract: Several cell types contribute to atherosclerotic calcification. Myeloid calcifying cells (MCCs) are monocytes expressing osteocalcin (OC) and bone alkaline phosphatase (BAP). Herein, we tested whether MCCs promote atherosclerotic calcification in vivo. We show that the murine spleen contains OC(+)BAP(+) cells with a phenotype similar to human MCCs, a high expression of adhesion molecules and CD11b, and capacity to calcify in vitro and in vivo. Injection of GFP(+) OC(+)BAP(+) cells into 8- or 40-week ApoE(-/-) mice led to more extensive calcifications in atherosclerotic areas after 24 or 4 weeks, respectively, compared to control OC(-)BAP(-) cells. Despite that OC(+)BAP(+) cells had a selective transendothelial migration capacity, tracking of the GFP signal revealed that presence of injected cells within atherosclerotic areas was an extremely rare event and so GFP mRNA was undetectable by qPCR of lesion extracts. By converse, injected OC(+)BAP(+) cells persisted in the bloodstream and bone marrow up to 24 weeks, suggesting a paracrine effect. Indeed, OC(+)BAP(+) cell-conditioned medium (CM) promoted calcification by cultured vascular smooth muscle cells (VSMC) more than CM from OC(-)BAP(-) cells. A genomic and proteomic investigation of MCCs identified allograft inflammatory factor (AIF)-1 as a potential candidate of this paracrine activity. AIF-1 stimulated VSMC calcification in vitro and monocyte-specific (CD11b-driven) AIF-1 overexpression in ApoE(-/-) mice increased calcium content in atherosclerotic areas. In conclusion, we show that murine OC(+)BAP(+) cells correspond to human MCCs and promote atherosclerotic calcification in ApoE(-/-) mice, through paracrine activity and modulation of resident cells by AIF-1 overexpression.
authors.affiliation: Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.forename: Marcello
authors.initials: M
authors.lastname: Rattazzi
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscaro
authors.forename: Roberta
authors.initials: R
authors.lastname: Cappellari
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.forename: Elisa
authors.initials: E
authors.lastname: Bertacco
authors.forename: Nicol
authors.initials: N
authors.lastname: Poncina
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dyar
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciciliot
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwabuchi
authors.forename: Renato
authors.initials: R
authors.lastname: Millioni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Arrigoni
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kraenkel
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002114:Calcinosis / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D022423:Myeloid Cells / Q000473:pathology / Q000502:physiology*; D015675:Osteocalcin / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C491049:Aif1 protein, mouse; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D015675:Osteocalcin; D000469:Alkaline Phosphatase; D002118:Calcium